Primary infection by varicella zoster virus (VZV) usually causes varicella (chickenpox), after which virus becomes latent in human ganglionic neurons along the entire neuraxis. With aging, a declining cell- mediated immunity to VZV leads to virus reactivation, manifesting as herpes zoster (shingles) characterized by pain and rash restricted to 1-3 dermatomes. The incidence and severity of zoster is also high in transplant recipients and patients with cancer or AIDS. Zoster is frequently complicated by chronic pain (postherpetic neuralgia), as well as paralysis, blindness and stroke. Currently, -1,000,000 Americans develop zoster annually. Oka VZV vaccine reduces the incidence of zoster by 50%, but even if every American over age 60 was vaccinated, >500,000 cases of zoster annually are still expected. VZV induces apoptosis in non-neuronal cells, but establishes latent infection in neurons. VZV ORFs 66, 62 and 63, which are expressed in latently infected human ganglia, and ORF 4 share homology with HSV-1 genes that have an anti-apoptotic function. We hypothesize that inhibition of apoptosis during VZV infection of neurons underlies neuronal survival and latency. BecauseVZV gene 63 is the most prevalent and abundant transcript expressed during latency, and the encoded protein (IE63) inhibits apoptosis in human neurons in culture, this project will focus primarily on the anti- apoptotic function of IE63 and its interaction with cellular anti-apoptotic proteins.
Aim 1 will dissect the cascade of apoptotic events in VZV-infected non-neuronal cells.
Aim 2 will develop a model of VZV latency in differentiated human neuronal cells to enable comparative analysis of expression profiles of cellular anti-apoptotic genes in cultured neuronal and non-neuronal cells to determine where in the caspase cascade apoptosis is inhibited in neurons.
Aim 3 will analyze interactions of VZV proteins expressed in latently infected human ganglia with cellular anti- apoptotic proteins. Understanding anti-apoptotic mechanism(s) in neuronal cells latently infected with VZV will help to identify molecular targets for therapeutic strategies to prevent and control the serious neurological complications of VZV reactivation.
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